1. Field of the Invention
The present invention relates to a hypotonic aqueous composition with reduced chloride content and with or without phospholipids for application in a method for the surgical or therapeutic treatment of the human or animal body or in a diagnostic method performed on the human or animal body. Particular emphasis is given to the use of the aqueous composition for application in a method for the therapeutic treatment of the human body, especially as amniotic fluid replacement, more particularly in amnioinfusion, preferably in the case of preterm premature rupture of membranes.
2. Related Technology
Preterm premature rupture of membranes (PPROM) is one of the main causes of perinatal morbidity and mortality. It occurs in 3% of all pregnancies and is responsible for a third of all premature births (Mercer B M. Preterm premature rupture of the membranes. Obstet Gynecol 2003; 101: 178-193). Important risk factors for PPROM are infections (Goldenberg R L, Culhane J F, Iams J D, Romero R. Epidemiology and causes of preterm birth. Lancet 2008; 371: 75-84), polyhydramnios (Simhan H N, Canavan T P. Preterm premature rupture of membranes: diagnosis, evaluation and management strategies. BJOG 2005; 112: 32-37), invasive prenatal diagnostics (Van Kamp I L, Klumper F J, Oepkes D, et al. Complications of intrauterine intravascular transfusion for fetal anemia due to material red-cell alloimmunization. Am J Obstet Gynecol 2005: 192: 171-177) and fetoscopic procedures (Gratacos E, Deprest J. Current experience with fetoscopy and the Eurofoetus Registry for fetoscopic procedures. Eur J Obstet Gynecol Reprod Biol 2000; 92: 151-159). In the event of occurrence of pulmonary hypoplasia, the perinatal mortality risk is about 80%.
The goal of therapeutic measures for the treatment of PPROM is to restore and to maintain the normal fluid volume in the amniotic cavity. To increase the amniotic fluid index (AFI), the fluid volume in the amniotic cavity is continuously increased by amnioinfusion (Tan L K et al. Test amnioinfusion to determine suitability for serial therapeutic amnioinfusion in midtrimester premature rupture of membranes. Fetal Diagn Ther 2003; 18: 183-189; Tranquillli A L et al. Transabdominal amnioinfusion in preterm premature rupture of membranes: a randomized controlled trial. BJOG 2005; 112: 759-763; Hsu T L et al. The experience of amnioinfusion for oligohydramnios during the early second trimester. Taiwan J Obstet Gynecol 2007; 46 (4)).
To replenish the fluid volume in the amniotic cavity, an isotonic salt solution is usually used in order to avoid any damage to the fetus as far as possible. Tested isotonic salt solutions include a physiological saline solution (0.9% by weight NaCl; osmolarity: 308 mosm/l), a Ringer's solution, a Ringer's lactate solution and a Ringer's acetate solution.
The Ringer's infusion solution contains:
8.60 g/l (147 mmol/l) NaCl
0.30 g/l (4.0 mmol/l) KCl and
0.33 g/l (2.2 mmol/l) CaCl2.
The Ringer's lactate solution contains:
5.9 g/l-6.1 g/l (125 mmol/l-134 mmol/l) NaCl
0.3 g/l-0.4 g/l (4.0 mmol/l-5.4 mmol/l) KCl
0.22 g/l-0.29 g/l (0.9 mmol/l-2.0 mmol/l) CaCl2*2H2O and
2.8 g/l-3.45 g/l (25 mmol/l-31 mmol/l) CH3CHOHCOONa.
Its theoretical osmolarity is between 262 mosm/l and 293 mosm/l.
The Ringer's acetate solution contains:
6.00 g/l (130 mmol/l) NaCl
0.40 g/l (5.4 mmol/l) KCl
0.134 g/l (0.9 mmol/l) CaCl2*2H2O
0.203 g/l (1.0 mmol/l) MgCl2*6H2O
3.70 g/l (27 mmol/l) CH3COONa*3H2O
Its theoretical osmolarity is 276 mosm/l.
The physiological saline solution has been found to be the most effective.
However, the currently known methods for amnioinfusion for treating PPROM are not satisfactory, since the fluid filled from the outside (isotonic salt solution) drains away again from the uterus very rapidly, thereby greatly reducing the effect of amnioinfusion. The known methods involved, for example, cervical occlusion with a fibrin gel (Zamlynski J, Bodzek P, Olejek A, Grettka K, Manka G. Results of amnioinfusion in pregnancies with oligohydramnios and non-ruptured fetal membranes. Med Wieku Rozwoj 2003; 7: 187-194) or the infusion of a fluid via a transcervical catheter (Machalski T, Sikora J, Bakon I, Magnucki J, Grzesiak-Kubica E, Szkodny E. Short-term and long-term fetal heart rate variability after amnioinfusion treatment of oligohydramnios complicated pregnancy. Ginekol Pol 2001; 72: 1107-1111).
Even repeated transabdominal amnioinfusions with physiological saline solution for the treatment of PPROM showed only minimal advantages in a treatment within 6 h after fluid loss (De Santis M, Scavo M, Noia G, Masini L, Piersigilli F, Romagnoli C, Caruso A. Transabdominal amnioinfusion treatment of severe oligohydramnios in preterm premature rupture of membranes at less than 26 gestational weeks. Fetal Diagn Ther 2003; 18: 412-417; Ogunyemi D, Thompson W. A case controlled study of serial transabdominal amnioinfusions in the management of second trimester oligohydramnios due to premature rupture of membranes. Eur J Obstet Gynecol Reprod Biol. 2002; 102: 167-172).
Against this background, long-term amnioinfusion of physiological saline solution by means of a subcutaneously implanted amniotic fluid replacement port system for the treatment of PPROM in humans has been proposed. This approach enabled pregnancy to be extended by several weeks while avoiding pulmonary hypoplasia (Tchirikov M, Steetskamp J, Hohmann M, Koelbl H. Long-term amnioinfusion through a subcutaneously implanted amniotic fluid replacement port system for treatment of PPROM in humans. Eur J Obstet Gynecol Reprod Biol. 2010; 152: 30-33).
Studies concerning the composition of amniotic fluid have also already been published. It is assumed that the phospholipids present in human amniotic fluid are responsible for fetal lung maturation (Lohninger A, Salzer H, Simbruner G, Husslein P, Martin G. Relationship among human amniotic fluid dipalmitoyl lecithin, postpartum respiratory compliance and neonatal respiratory distress syndrome. Clin. Chem. 1983; 29: 650-655; Almog R, Anderson-Samsonoff C, Berns D S, Saulsbery R. A methodology for determination of phospholipids. Analytical Biochemistry 1990; 188: 237-242). Corresponding preparations based on phospholipids from bovine lung have been available on the market for some time for the treatment of premature babies suffering from respiratory distress syndrome (ALVEOFACT®, SURVANTA®).
ALVEOFACT® contains, per 1.2 ml, 50.76 mg-60 mg of phospholipid fraction from bovine lung (surfactant; corresponds to 50 mg of total phospholipids) and also sodium chloride and sodium hydrogencarbonate (Rote Liste 2000).
SURVANTA® contains, per 8 ml, 72.8 mg-211.2 mg of phospholipid fraction from bovine lung, 18.4 mg-157.6 mg of 1,2-dipalmitoyl-sn-glycero-3-phosphocholine, 1.4 mg-11.1 mg of palmitic acid, 2.2 mg-10.5 mg of glyceryl tripalmitate (corresponds to 50 mg of total phospholipids) and also sodium chloride and sodium hydrogencarbonate or hydrochloric acid (Rote Liste 2000).
It has been further found that the concentration of surfactant proteins changes in the event of intraamniotic infections (Chaiworapongsa T, Hong J S, Hull W M, Romero R, Whitsett J A. Amniotic fluid concentration of surfactant proteins in intra-amniotic infection. J Matern Fetal Neonatal Med. 2008; 21: 663-670) and falls in the case of spontaneous childbirth on the expected date of birth (Chaiworapongsa T, Hong J S, Hull W M, Kim C J, Gomez R, Mazor M, Romero R, Whitsett J A. The concentration of surfactant protein-A in amniotic fluid decreases in spontaneous human parturition at term. J Matern Fetal Neonatal Med. 2008; 21: 652-659).
Furthermore, our studies have revealed that the osmolarity, i.e., the number of osmotically active particles per liter of solution, in human amniotic fluid is lower than in physiological saline solution (308 mosm/l). In addition, the chloride ion concentration in amniotic fluid is also distinctly lower than in physiological saline solution.
Against this background, it has to be assumed that amnioinfusion, more particularly long-term amnioinfusion, with a physiological saline solution, as currently favored according to the prior art, is disadvantageous for a fetus for several reasons:
Firstly, the administration of an infusion solution having an excessively high osmolarity increases the osmolarity of the amniotic fluid, which is continually drunk and excreted by the fetus. Particularly in the case of long-term administration of the infusion solution, this can cause damage to the organs of the fetus, especially its skin, its eyes and its digestive organs, more particularly its kidneys. In addition, there is reason to fear a change in the fetal programming which might lead to hypertension in later life, even if this has so far not yet been described owing to lack of relevant data.
A similar argument applies to the administration of an infusion solution having an excessively high chloride ion concentration. It increases the chloride ion concentration of the amniotic fluid, which is continually drunk and excreted by the fetus. Particularly in the case of long-term administration of the infusion solution, this can cause damage to the organs of the fetus, especially its skin, its eyes and its digestive organs, more particularly its kidneys. In addition, there is reason to fear a change in the fetal programming which might lead to problems in later life, even if this has so far not yet been described owing to lack of relevant data.
Furthermore, the administration of an infusion solution which does not contain any phospholipids lowers the concentration of the phospholipids in the amniotic fluid, which is in continuous contact with the alveoli of the fetus. Particularly in the case of long-term administration of the infusion solution, this can lead to rinsing out of the phospholipids on the alveoli of the fetus and thus to slowing of lung maturation in the fetus. As a result, the chances of survival for such a fetus are distinctly reduced.
In addition, the administration of an infusion solution which does not contain any surfactant proteins lowers the concentration of the surfactant proteins in the amniotic fluid. Particularly in the case of long-term administration of the infusion solution, this can lead to damage to the organs of the fetus.
From the prior art, fetoscopic procedures are also known in which the amnion is opened, the amniotic fluid is at least partly removed, the fetus is operated on, the amnion is reclosed, and the removed amniotic fluid is at least partly returned to the amniotic cavity.
For medical and ethical reasons, it is not possible to use the amniotic fluid removed in this manner for the treatment of PPROM in other patients. Firstly, the fetus that has been operated on requires the amniotic fluid after the operation in order to increase its chances of survival. Furthermore, the removed amniotic fluid contains tissue remnants and considerable amounts of DNA from the fetus that has been operated on (J Cln Endocrinol Metab 2000; 85: 214-8 “Large amounts of cell-free fetal DNA are present in amniotic fluid”). Amniotic fluid can, for example, contain 778 fetal cells and more in 1 mm3. These tissue remnants and this large amount of DNA can lead to unwanted reactions to the genetically foreign material and/or to infections in another fetus or its mother.
For similar reasons, it is, without hesitation, also not possible to use animal amniotic fluid for the treatment of PPROM in humans. Firstly, owing to the tissue remnants and large amounts of DNA of the animal fetus that are present in this amniotic fluid, there is reason to fear unwanted reactions of the fetus and/or of the mother to the genetically foreign material and/or infections. In addition, there is the possible risk of formation of chimeras as a result of mixing of genetic information, which is prohibited in most countries by law.
The publication by Brace R A et al., Amniotic fluid volume responses to amnio-infusion of amniotic fluid versus lactated Ringer's solution in fetal sheep. J Soc Gynecol Investig. 2004, 11(6): 363-368, describes amnioinfusion of amniotic fluid in pregnant sheep, the amniotic fluid used having previously been obtained from other sheep fetuses.
However, when using amniotic fluid from sheep in amnioinfusion in another mammal, more particularly in humans, there is a considerable risk of hereditary material from the animal, for example the DNA of the sheep, being incorporated into the DNA of the fetus and so-called chimeras being formed. Therefore, it is not meaningful to use animal amniotic fluid in amnioinfusion in another mammal, more particularly in humans, especially since the production of chimeras is prosecutable in most countries.
Furthermore, it would not be meaningful to use amniotic fluid from sheep for long-term amnioinfusions due to PPROM in other mammals, more particularly in humans, who are the focus of the present invention. For instance, a human fetus drinks between 200 ml and 700 ml of amniotic fluid every day and the skin and also the mucous membranes of the fetus are partially permeable for the surrounding amniotic fluid. In the case of PPROM, it is necessary to infuse about 2 liters of amniotic fluid every day over several months. If it should be seriously contemplated that this large amount of amniotic fluid be obtained from animals for these purposes, there is the risk, in some cases, of infections being transmitted directly from the animals to the fetus and also to the expectant mother. There is reason to fear this, especially for infections which cannot be completely avoided by means of sterilization of the animal amniotic fluid, for example prion transmission.
Apart from that, the sodium ion concentration (121.4 mmol/L) and the calcium ion concentration (0.75 mmol/L) in ovine amniotic fluid are significantly lower than in human amniotic fluid (Gesteland K M et al. Intramembranous solute and water fluxes during high intramembranous absorption rates in fetal sheep with and without lung liquid diversion. American Journal of Obstetrics & Gynecology, 2009 85.e1-85.e6; Ross M G et al. Amniotic fluid ionic concentration in response to chronic fetal vasopressin infusion. American Physiological Society 1985 E287-E291).
The publication by Corpening J W et al., Ingested bovine amniotic fluid enhances morphine antinociception in rats. Physiology & Behavior 2000 (70) 15-18, concerns the administration of bovine amniotic fluid to rats.
However, when using bovine amniotic fluid in amnioinfusion in other mammals, for example rats, there is a considerable risk of bovine hereditary material being incorporated into the DNA of the fetus and so-called chimeras being formed. Therefore, it is not meaningful to use bovine amniotic fluid in amnioinfusion in other mammals, more particularly in humans, especially since the production of chimeras is prosecutable in most countries.
The publication by Doi S et al., Effect of Maternal Hydration on Oligohydramnios: A Comparison of Three Volume Expansion Methods. Obstetrics & Gynecology 1998, 92 (4), 525-529, studies the influence of intravenous administration of an isotonic fluid or of a hypotonic fluid and also of an oral administration of water on the amniotic fluid index (AFI) in women. The hypotonic solution used is Ringer's solution. It has an excessively high chloride ion concentration with the associated disadvantages (see above).
The patent application EP 1 719 517 A1 relates to an artificial physiological saline solution having an osmolarity in the range from 260 mOsm/l to 320 mOsm/l, which preferably contains not more than 200 mmol/l chloride ions. However, the chloride ion concentration is much higher than required here. Concerning the disadvantages of an excessively high chloride ion concentration, reference is made to the above explanations.
The patent application EP 0 998 916 A1 is concerned with medical compositions for administration across the mucous membrane. The compositions are said to have an osmolarity lower than 290 mOsm/l. However, the only example with an osmolarity in the range required here has an excessively high chloride ion concentration. Concerning the disadvantages of an excessively high chloride ion concentration, reference is again made to the above explanations.